The K26 Award will be utilized to devote 50% effort to research in mouse pathobiology and to mentoring veterinarians and PhD graduate students in Veterinary Biosciences and other graduate programs at OSU in experimental pathophysiology of mouse models of human disease. There will be four major research projects: 1) develop a mammary gland-specific 'knock-out' model to investigate the function of parathyroid hormone-related protein (PTHrP) during lactation and in the neonate during suckling (ongoing project); 2) investigate the pathogenesis of humoral hypercalcemia of malignancy in a new SCID/beige mouse model of human HTLV-1-associated lymphoma (ongoing project); 3) investigate the pathogenesis of bone formation induced by bone metastases of human prostate cancer ("osteoblastic" metastases) by xenotransplantation of prostate epithelial cells in bones of athymic mice (new project); and 4) examine the effects of disruption (knock-out) of the genes for estrogen receptor alpha and beta on bone remodeling in normal, ovariectomized, and estrogen-treated mice (new collaborative project). The models have been carefully chosen and developed to mimic human disease and to provide unique opportunities to gain knowledge and train mouse pathobiologists in areas that are poorly understood, namely bone disease, cancer in bone, osteoporosis, and humoral hypercalcemia of malignancy. The projects will build on the long-term expertise of the applicant's laboratory in the pathophysiology of bone, cancer, and hypercalcemia in mice. Mentorship will consist of: 1) serving as advisor for veterinarians pursuing a PhD in experimental mouse pathobiology (currently advisor for five DVMs); 2) serving as collaborative mentor on research projects by veterinarians and basic scientist PhD candidates in the Department of Veterinary Biosciences (currently 17 projects) and PhD candidates in the Molecular, Cellular, and Developmental Biology Program and Comprehensive Cancer Center at OSU; 3) participating in training programs offered by the Transgenic Animal Shared Resource; 4) collaborating on research projects involving experimental pathobiology of mice; and 5) developing a training program in mouse pathobiology.